期刊
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
卷 94, 期 3, 页码 454-463出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbb.2009.10.008
关键词
Methotrexate; Spatial memory; Homocysteine; S-adenosylmethionine; S-adenosylhomocysteine; Cerebrospinal fluid
资金
- Damon Runyon Cancer Research Foundation [CI-16-03]
Purpose: Although most children with acute lymphoblastic leukemia (ALL) are cured, a subset manifests persistent. focal cognitive deficits. Methotrexate (MTX), a key component of leukemia treatment, is suspected to contribute to treatment-induced cognitive dysfunction. We sought to establish a rodent model in order to further investigate the underlying pathophysiology. Procedures: Intraperitoneal MTX was given to Long-Evans rats on two schedules: acute (250 mg/kg once during adulthood), or chronic (1 mg/kg twice weekly x4 doses, beginning at postnatal day 15, then weekly x6). Control rats were given saline injections on the same schedules. All male rats subsequently underwent behavioral testing designed to assess cognitive domains frequently impaired among children treated for ALL. Cerebrospinal fluid and serum folate concentrations were measured by HPLC. Findings: Both acute and chronic MTX administration produced spatial memory deficits, without significantly altering visual memory, general exploration. activity or motor coordination. MTX administration was also associated with a marked reduction in serum and CSF folate and a decrease in the ratio of CSF S-adenosylmethionine to S-adenosylhomocysteine. Conclusions: Similar to children treated for ALL rats given systemic MTX develop focal cognitive deficits along with expected alterations in folate physiology. (C) 2009 Elsevier Inc. All rights reserved.
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